Streptovaricinone C derivatives as antibiotics

ABSTRACT

Streptovaricinone C derivatives of the formula ##STR1## wherein Z is a C 1   -12  alkyl, an aryl, a hydroxyalkyl, an alkenyl, a ketonyl, a furyl-oxoalkyl, a thienyl-oxoalkyl, a phenacyl, a carbamylalkyl, a benzyl, a phenoxyalkyl, a cyanoalkyl, a phenethyl, a benzoyloxyethyl, a p-chlorophenacyl, a p-methoxyphenacyl, a p-nitrobenzyl, a p-methylbenzyl, an alkanoyl, a benzoyl, a benzenesulfonyl, an alkylsulfonyl or an alkoxycarbonyl group, are antibiotics.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to novel antibiotics of streptovaricinoneC derivatives.

2. Description of the Prior Art

Streptovaricins are known antibiotics produced by culturing the strainof Streptomyces 101, species 2494. The chemical formula ofstreptovaricins has been confirmed to be: ##STR2##

The present inventors have discovered that streptovaricin C having theformula (I) can be hydrolyzed in an alkaline medium under oxidizingconditions to produde a streptovaricinone having the formula: ##STR3##

Consequently, it would be most desirable to have additional antibioticshaving this new basic structure.

SUMMARY OF THE INVENTION

Accordingly, it is an object of the present invention to provide novelantibiotics which have excellent antibiotic activity.

It is another object of this invention to provide a process forproducing these novel antibiotics.

Briefly, these and other objects of this invention, as will hereinafterbecome clear from the ensuing discussion, have been attained byproviding novel antibiotics of streptovaricinone C derivatives havingthe formula: ##STR4## wherein Z, represents a C₁₋₁₂ alkyl, an aryl, ahydroxyalkyl, an alkenyl, a ketonyl, a furyl-oxoalkyl, athienyl-oxoalkyl, a phenacyl, a carbamylalkyl, a benzyl, a phenoxyalkyl,a cyanoalkyl, a phenethyl, a benzoyloxyethyl, a p-chlorophenacyl, ap-methoxyphenacyl, a p-nitrobenzyl, a p-methylbenzyl, an alkanoyl, abenzoyl, a benzenesulfonyl, an alkylsulfonyl or an alkoxycarbonyl group.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The streptovaricinone C derivatives of this invention can be produced byetherification or esterification of streptovaricinone C having theformula (II). The etherification of streptovaricinone C can be conductedby reacting a Z-hal (Z is the desired substituent and hal is a halogensuch as Cl, Br or I) in the presence of silver oxide in a solvent suchas methanol, ethanol, ether, 1,2-dimethoxyethane, tetrahydrofuran, andthe like. The streptovaricinone C is dissolved and suspended in thesolvent, and 0.5 - 5 mole equivalents of silver oxide are added. Themixture is stirred at room temperature for from 30 minutes to 24 hoursto form a suspension of the salt, e.g., the silver salt. Excess of ahalide having the formula Z is added to the suspension of the salt whilestirring the reaction. The reaction can usually be conducted at roomtemperature for about from 30 minutes to 72 hours, whereby the hydroxylgroup at the 6-position is etherified. In some cases, the hydroxylgroups at the 8-and/or 27-positions can be etherified. It is alsopossible to etherify the hydroxy group at the 6-position by adding alarge excess of a diazoalkane in a solvent to a solution ofstreptovaricinone C and reacting them at room temperature.

The product can be separated and purified by conventional methods. Forexample, the reaction mixture can be filtered to remove the precipitateof silver halide and the filtrate then condensed and dried at 35°- 45° Cunder a reduced pressure. The residue is extracted by an organicsolvent, washed with a dilute solution of sodium bicarbonate andpurified by chromatography or recrystallization.

when acetone halide is used as the Z-hal, 6-0-acetonylstreptovaricinoneC is obtained. 6-0-acetonylstreptovaricinone C can then be converted tostreptovaricinone C derivatives having the formula: ##STR5## or ##STR6##wherein R represents a hydroxyimino group, a substituted hydroxyiminogroup or a hydrazono group by reacting it with hydroxylamine in thepresence of a strong acid.

an O-substituted hydroxylamine such as O-methylhydroxylamine,O-ethylhydroxylamine; or a substituted hydrazine such as1-methylhydrazine, 1-ethylhydrazine,1,1-dimethylhydrazine,1,1-diethylhydrazine, 1,1-dipropylhydrazine,1,1-dibutylhydrazine, 1,1-dibenzylhydrazine, 1-methyl-1-phenylhydrazine,benzylidenehydrazine, cyclohexylidenehydrazine, N-aminopiperidine,N-aminomorpholine, N-amino-N'-methylpiperazine and the like, or ahydrochloride thereof.

The reaction is preferably conducted in an inert organic solvent such asbenzene, methanol, tetrahydrofuran, especially in methanol under strongacidic conditions, especially using hydrochloric acid. In order toproduce compound (IV), it is preferred to employ a molar ratio of thehydroxylamine or the hydrazine to 6-0-acetonylstreptovaricinone C of1.5 - 5, at room temperature while stirring for from 3 minutes to 3hours. The progress of the reaction can be determined by silica gel thinlayer chromatography.

The products can be separated and purified by conventional methods. Forexample, the reaction mixture can be extracted with an organic solventand purified by chromatography or recrystallization. In order to producecompound (VI), it is preferred to use a molar ratio of the hydroxylamineor the hydrazine to 6-0-acetonylstreptovaricinone C of about 10,especially in the presence of an excess of acetic acid, at roomtemperature for 0.5 - 2 hours.

6-0-ketonylstreptovaricinone C can be converted by intramolecular aldolcondensation to produce a streptovaricinone C derivative having theformula: ##STR7## wherein R' represents a lower alkyl group containingup to 6 carbon atoms such as a methyl or ethyl group; an aromaticresidual group such as a phenyl group; a heterocyclic residual group,such as a 2-furyl group, an α-thienyl group, and substituted derivativesthereof, such as those having lower alkyl group, lower alkoxyl group,hydroxyl group, nitro group or halogen substituents.

The intramolecular aldol condensation can be conducted by adding anorganic base to 6-0-ketonylstreptovaricinone C in the presence of anexcess of acid in an organic solvent. The organic solvent is preferablybenzene. The acid is preferably an organic acid, e.g., acetic acid. Theorganic base is preferably a primary amine or a secondary amine,especially benzylamine. The reaction is usually conducted at roomtemperature for from 0.5 to 24 hours. When benzylamine is used as theorganic base, the reaction velocity is effectively high. The6-0-ketonylstreptovaricinone C can be produced by reacting a halidehaving the formula R--CO--CH₂ --hal with steptovaricinone C as describedabove.

The esterification of streptovaricinone C can be conducted by reactingan alkali metal salt of streptovaricinone C with an organic acyl halide,an organic sulfonyl halide or an alkyl halocarbonate. The hydroxyl groupat the 6-position can be converted to a Z'0-group wherein Z' representsan alkenoyl group, a benzoyl group, a benzenesulfonyl group, analkylsulfonyl group or an alkoxycarbonyl group which can also have inertsubstituents.

Suitable organic acyl halides, organic sulfonyl halides and alkylhalocarbonate include fatty acid halides, benzoil acid halides,benzenesulfonic acid halides, alkylsulfonic acid halides, methylchlorocarbonates, and the like. The reaction is preferably conducted inan inert organic solvent such as tetrahydrofuran by adding said halidein a 1-3 molar ratio relative to the amount of alkali metal salt ofstreptovaricinone C while stirring at room temperature for from 5minutes to 48 hours.

The streptovaricinone C derivatives of this invention have effectivepharmacological properties, especially high antibiotic activity to Grampositive bacteria. The streptovaricinone C can be administered in thesame fashion as other streptovaricin antibiotics, such as in the form ofa tablet, a sugar-coated tablet, a powder, an ointment, a cream, acapsule, a solution suspension, an emulsion, and in other conventionalways. It can be administered in conjuction with a pharmaceuticallyacceptable carrier such as an organic or inorganic solid or liquidcarrier. The dose of the streptovaricinone C derivatives of thisinvention should be in the range of from 100 l mg to 3 g per day. Properdosages can be determined using conventional considerations.Pharmacological compositions can also contain other conventionaladditives and pharmaceutically active ingredients.

The following tables contain the melting points and antibiotic activityof many typical streptovaricinone C derivatives. This list is notintended to be limiting in any way, but is presented for illustrativepurposes only.

In vitro microbial activity:

The microbial activity was determined using standard methods accordingto the Japanese Chemotherapy Society. A solution of 10 mg of a drug in 1ml of ethanol was diluted with 9 ml of 0.01% aq. Tween 80 solution, andthe solution was further separately diluted with the same diluent toconcentrations of 1,000, 500, 200, 100 and lower μ g/ml.

A mixture of 9 ml of warm brain heart infusion agar broth and 1 ml ofthe above drug solution was placed in a Petri plate and cooled to roomtemperature. All test organisms such as Staphylococcus aureus RosenbachFDA 209 P JC-1 and Bacilus subtilis ATCC 6633 were incubated at 37° Cfor 18-20 hours in Trypto-Soy broth (Eiken) and adjusted to 1:10⁸inoculum, except for Mycobacterium smegmatis ATCC 607 which wasincubated at 37° C for 48 hours in brain heart infusion agar brothcontaining 5% glycerol.

The above bacterial solution was streaked on the Petri agar platecontaining the drug and incubated at 37° C for 18-20 hours, except forMycobacterium smegmatis 607 which was incubated for 48 hours at 37° C.The bacterial solution of Mycobacterium tuberculosis H37Rv was preparedin the homogenized Tween solution after which it was adjusted to a 0.1mg/ml solution by turbidimetry. A mixture of 4.5 ml of Kirchnersemiliquid agar solution, 0.5 ml of horse serum and 0.5 ml of Tweensolution was used for the incubation of this bacterium. One-tenth ml ofsaid bacterial solution was seeded and incubated at 37° C for two weeks.The minimum inhibitory concentration (MIC) was the lowest concentrationof the drug which prevented visible growth after incubation.

                                      Table 1                                     __________________________________________________________________________    6-O-substituted streptovaricinones C shown by the formula III                                         Antibiotic activity μg/ml                                                              Myco. Myco.                                                Melting                                                                              St. aureus                                                                          Bacilus                                                                             smeg. tuberc.                             Z                point (° C)                                                                   209 P subtilis                                                                            607   H37Rv                               __________________________________________________________________________      H(Reference)   284-285                                                                              50    > 100 > 100 > 100                               1 CH.sub.3       165-167                                                                              1     10    20    10                                  2 CH.sub.3 CH.sub.2                                                                            156-158                                                                              1     0.5   20    50                                  3 CH.sub.3 CH.sub.2 CH.sub.2                                                                   163-164                                                                              10    5     5     20                                  4 CH.sub.3 CH.sub.2 CH.sub.2 CH.sub.2                                                          154-155                                                                              10    5     20    50                                  5 CH.sub.3 (CH.sub.2).sub.4                                                                    148-149                                                                              10    5     5     20                                  6 (CH.sub.3).sub.2 CHCH.sub.2 CH.sub.2                                                         150-152                                                                              10    5     20    50                                  7 CH.sub.3 (CH.sub.2).sub.5                                                                    131-133                                                                              5     2     2     20                                  8 CH.sub.3 (CH.sub.2).sub.6                                                                    128-130                                                                              2     --    0.5   10                                  9 ClCH.sub.2 CH.sub.2                                                                          156-158                                                                              1     1     --    20                                  10                                                                              ClCH.sub.2 CH.sub.2 CH.sub.2                                                                 145-147                                                                              5     2     20    10                                  11                                                                              CH.sub.2CHCH.sub.2                                                                           155-156                                                                              2     1     20    20                                  12                                                                              HOCH.sub.2 CH.sub.2 CH.sub.2                                                                 140-141                                                                              5     5     0.5   20                                  13                                                                              PhOCH.sub.2 CH.sub.2                                                                         142-144                                                                              2     --    0.5   5                                   14                                                                              NCCH.sub.2 CH.sub.2 CH.sub.2                                                                 158-160                                                                              10    20    5     10                                  15                                                                              CH.sub.3 COCH.sub.2                                                                          162-163                                                                              1     2     --    10                                  16                                                                              PhCOCH.sub.2   144-146                                                                              5     20    20    20                                  17                                                                               ##STR8##      163-165                                                                              0.5   --    20    10                                  18                                                                               ##STR9##      162-165                                                                              5     --    10    5                                   19                                                                               ##STR10##     154-156                                                                              10    --    2     20                                  20                                                                               ##STR11##     153-155                                                                              5     5     5     10                                  21                                                                               ##STR12##     155.156                                                                              2     --    0.5   5                                   22                                                                               ##STR13##     136-138                                                                              5     --    0.5   2                                   23                                                                               ##STR14##     162-164                                                                              5     --    1     5                                   24                                                                               ##STR15##     144-146                                                                              10    5     10    20                                  25                                                                               ##STR16##     145-147                                                                              5     --    1     50                                  26                                                                              CH.sub.3 CO    169-171                                                                              20    --    --    5                                   27                                                                              CH.sub.3 CH.sub.2 CO                                                                         160-162                                                                              10    --    --    20                                  28                                                                              CH.sub.3 CH.sub.2 CH.sub.2 CO                                                                156-157                                                                              20    --    --    5                                   29                                                                              CH.sub.3 (CH.sub.2).sub.3 CO                                                                 153-156                                                                              2     --    --    5                                   30                                                                              CH.sub.3 (CH.sub.2).sub.4 CO                                                                 144-147                                                                              2-5   --    --    10                                  31                                                                              BrCH.sub.2 CO  165-168                                                                              10    --    --    5                                   32                                                                              PhCH.sub.2 CO  154-155                                                                              20    --    --    5                                   33                                                                              CH.sub.3 (CH.sub. 2).sub.3 SCH.sub.2 CO                                                      132-134                                                                              5     --    --    0.5                                 34                                                                               ##STR17##     150-153                                                                              10    --    --    1                                   35                                                                               ##STR18##     139-142                                                                              10    --    --    1                                   36                                                                               ##STR19##     142-144                                                                              10    --    --    0.5                                 37                                                                               ##STR20##     134-136                                                                              5     --    --    1                                   38                                                                              CH.sub.3 SO.sub.2                                                                            167-170                                                                              1     --    --    2                                   39                                                                               ##STR21##     156-158                                                                              2     --    --    5                                   40                                                                               ##STR22##     162-165                                                                              1     --    --    1                                   41                                                                               ##STR23##     165-167                                                                              5     --    --    2                                   42                                                                               ##STR24##     180-184                                                                              5     --    --    2                                   43                                                                              CH.sub.3 OCO   160-163                                                                              2     --    --    10                                  44                                                                              CH.sub.3 CH.sub.2 OCO                                                                        152-154                                                                              2     --    --    1                                   45                                                                              (CH.sub.3).sub.2 CHCH.sub.2 OCO                                                              150-152                                                                              0.2   --    --    5                                   46                                                                              CH.sub.3 (CH.sub.2).sub.3 OCO                                                                138-141                                                                              1     --    --    1                                   47                                                                               ##STR25##     164-165                                                                              5     --    --    1                                   48                                                                               ##STR26##     186-188                                                                              5     --    --    1                                   __________________________________________________________________________

                                      TABLE 2                                     __________________________________________________________________________    6-O-substituted streptovaricinones C, shown by the formula IV:                                          Antibiotic activity μg/ml                                                  St.      Myco.                                                                             Myco.                                                   Melting  aureus                                                                            Bacilus                                                                            smeg.                                                                             tuberc.                                R                point (° C)                                                                     209P                                                                              subtilis                                                                           607 H37Rv                                  __________________________________________________________________________    49 NOH           166-167  0.2 100  20  5                                      50 NOCH.sub.3    145-147  0.5 0.5  50  20                                     51 NOC.sub.2 H.sub.5                                                                           142-144  0.5 --   --  5                                      52 NOnC.sub.3 H.sub.7                                                                          138-140  5   --   --  20                                     53 NOnC.sub.4 H.sub.9                                                                          130-132  2   --   --  2                                      54 NOnC.sub.5 H.sub.11                                                                         129-132  1   --   --  2                                      55 NOnC.sub.6 H.sub.13                                                                         124-126  2   --   --  10                                     56 NOnC.sub.9 H.sub.19                                                                         106-109  10  --   --  5                                      57 NOCH.sub.2 CHCH.sub.2                                                                       132-134  2   --   --  20                                     58 NOCH.sub.2 Ph 144-145  2   --   --  10                                     59 NOCH.sub.2 CH.sub.2 OOCPh                                                                   110-113  0.5 --   --  2                                      60 NOCH.sub.2 CH.sub.2 OPh                                                                     106-109  0.5 --   --  2                                      61 NNHCONH.sub.2 236-237  0.5 0.5  50  20                                     62                                                                                ##STR27##    182-183  1   1    20  10                                     __________________________________________________________________________

                                      Table 3                                     __________________________________________________________________________    6-O-substitute streptovaricinones C, shown by the formula V:                                           Antibiotic activity μg/ml                                                  St.        Myco Myco                                                 Melting  aureus                                                                              Bacilus                                                                            smeg.                                                                              tuberc.                              R               point (° C)                                                                     209P  subtilis                                                                           607  H37Rv                                __________________________________________________________________________    63 NOH          189-190  0.2   100  20   5                                    64 NNHMe        170-171  0.2   --   --   10                                   65 NN(Me).sub.2 166-167  0.2   100  50   20                                   66 NNHCH.sub.2 CH.sub.2 OH                                                                    170-171  0.2   --   --   20                                   67 NN(n-C.sub.3 H.sub.7).sub.2                                                                154-155  0.2   --   10   20                                   68 NN(n-C.sub.4 H.sub.9).sub.2                                                                140-141  0.2   --   50   20                                   69 NN(n-C.sub.5 H.sub.11).sub.2                                                               132-133  <0.1  --   10   20                                   70 NN(n-C.sub.6 H.sub.13).sub.2                                                               122-123  2     --   --   > 50                                 71 NN(n-C.sub.8 H.sub.17).sub.2                                                               97-98    1     --   --   > 50                                 72 NN(CH.sub.2 CHCH.sub.2 ).sub.2                                                             148-149  1     --   --   20                                   73 NN(Me)Ph     156-157  5     --   > 50 > 100                                74 NN(Et)Ph     153-154  2     --   > 100                                                                              > 100                                75 NNCHPh       166-167  0.2   --   > 100                                                                              50                                   76                                                                                ##STR28##   174-175  1     --   20   20                                   77                                                                                ##STR29##   173-174  2     --   50   20                                   78                                                                                ##STR30##   165-166  0.5   --   20   20                                   79                                                                                ##STR31##   170-171  0.5   0.5  50   20                                   80                                                                                ##STR32##   162-163  0.5   --   20   20                                   81                                                                                ##STR33##   184-185  0.2   --   20   20                                   82                                                                                ##STR34##   167-170  < 0.1 --   20   20                                   83                                                                                ##STR35##   167-168  0.2   --   20   20                                   84                                                                                ##STR36##   170-171  0.2   --   20   20                                   __________________________________________________________________________

                                      Table 4                                     __________________________________________________________________________    6-O-substituted streptovaricinones C, shown by the formula VI:                                     Antibiotic activity μg/m                                                   St.      Myco.                                                                             Myco.                                                   Melting  aureus                                                                            Bacilus                                                                            smeg.                                                                             tuberc.                                     R'          point (° C)                                                                     209P                                                                              subtilis                                                                           607 H37Rv                                       __________________________________________________________________________    85 CH.sub.3 162-163  0.2 0.5  50  100                                         86 CH.sub.3 CH.sub.2                                                                      161-163  10  --   --  10                                          87                                                                                ##STR37##                                                                             164-166  2   2    --  50                                          88                                                                                ##STR38##                                                                             159-162  10  --   --  10                                          89                                                                                ##STR39##                                                                             162-165  5   --   --  10                                          90                                                                                ##STR40##                                                                             163-165  2   --   --  20                                          91                                                                                ##STR41##                                                                             168-170  5   --   --  10                                          __________________________________________________________________________

Having generally described the invention, a more complete understandingcan be obtained by reference to certain specific Examples, which areprovided herein for purposes of illustration only and are not intendedto be limiting unless otherwise specified.

EXAMPLE 1 Preparation of 6-0-methylstreptovaricinone C

To a suspension of 1.42 g of streptovaricinone C in 70 ml of methanolwas added 400 mg of silver oxide, and the mixture was stirred at roomtemperature for 1 hour. To the resultant mixture was added 3 g of methyliodide, and the reaction mixture was stirred at room temperature for 1hour and filtered through Celite. The filtrate was evaporated underreduced pressure to dryness to give a red oil. The oil wasrecrystallized from acetone-n-hexane as yellow needles, m.p. 165°-167°C, affording a single spot on silica gel t.l.c. The yield was 860 mg.

EXAMPLE 2 Preparation of 23, 24-dihydro-6-0-methylstreptovaricinone C

To a suspension of 50 mg of streptovaricinone C in 5 ml oftetrahydrofuran was added 20 ml of diazomethane-ether solution whilecooling in an ice-water bath for 30 minutes. Thereafter, a few drops ofacetic acid were added. The reaction mixture was evaporated to drynessunder reduced pressure, and the residue was dissolved in a small amountof ethyl acetate. To the solution was added a large amount of n-hexaneto give a yellow precipitate which was recrystallized fromacetone-n-hexane to yield 25 mg of 6-0-methylstreptovaricinone C,melting at 165°-167° C. The product showed the same Rf value as the oneobtained in Example 1 on silica gel t.l.c.

EXAMPLE 3 Preparation of 23,24-dihydro-6-0-methylstreptovaricinone C

To a solution of 50 mg of 23,24-dihydrostreptovaricinone C in 3 ml ofmethanol was added 17 mg of silver oxide while stirring at roomtemperature for 30 minutes. To the resultant mixture was added 1 ml ofmethyl iodide, and the reaction mixture was stirred at room temperaturefor 30 minutes, and then filtered. The filtrate was evaporated underreduced pressure to give a red oil. The oil was chromatographed onSephadex LH-20 with acetone, and the appropriate fractions werecollected and evaporated to dryness under reduced pressure. Theresulting oil was recrystallized from chloroform-n-hexane to yield 31 mgof yellow crystalline powder, melting at 135°-137° C.

EXAMPLE 4 Preparation of 6-0-phenacylstreptovaricinone C

To a suspension of 713 mg of streptovaricinone C in 80 ml of methanolwas added 1.16 g of silver oxide, and the mixture was stirred at 20° Cfor 2 hours. To the resulting mixture was added 2 g of-bromo-acetophenone, and the reaction mixture was stirred at roomtemperature for 18 hours, and filtered through Celite. The filtrate wasevaporated to dryness under reduced pressure to give a red oil. The oilwas chromatographed on Sephadex LH-20 with acetone, and the appropriatefractions were collected, and evaporated to dryness under reducedpressure. The resulting oil was recrystallized from acetone-n-hexane toafford 338 mg of yellow needles of 6-0-phenacylstreptovaricinone C, m.p.155°-157° C.

EXAMPLE 5 Preparation of 6-0-cyclohexylstreptovaricinone C

To a suspension of 570 mg of streptovaricinone C in 50 ml of methanolwas added 928 mg of silver oxide, and the mixture was stirred at 25° Cfor 3 hours. To the resultant mixture was added 3.26 g of cyclohexylbromide. The reaction mixture was stirred at 25° C for 18 hours and then928 mg more of silver oxide was added and the mixture was stirred at 50°C for 10 minutes. To the mixture was added 3.26 g more of cyclohexylbromide, and stirring extended for 1 hour at room temperature. Themixture was then filtered, and the filtrate was evaporated to drynessunder reduced pressure. The resulting oil was dissolved in 150 ml ofethyl acetate, and the solution was washed with 5% sodium bicarbonatesolution. The organic layer was separated, and evaporated to drynessunder reduced pressure to give a red oil which was chromatographed onsilica gel with 3% methanol in chloroform. The appropriate fractionswere collected and evaporated to dryness under reduced pressure to givea red oil which was recrystallized from chloroform-n-hexane as 185 mg of6-0-cyclohexylstreptovaricinone C, m.p. 164°-165° C.

EXAMPLE 6 Preparation of 6-0-(3'-chloro-propyl)streptovaricinone C

To a suspension of 120 mg of streptovaricinone C in 10 ml of methanolwas added 120 mg of silver oxide, and the mixture was stirred at roomtemperature for 1 hour. Then, to the mixture was added 1.5 g of1-chloro-3-bromopropane, and the reaction mixture was stirred at roomtemperature for 40 hours. The reaction mixture was then filtered throughCelite, and the filtrate was evaporated to dryness under reducedpressure. The residue was chromatographed on silica gel with 4% methanolin chloroform, and the appropriate fractions were collected, andevaporated to dryness under reduced pressure to give a red oil which wasrecrystallized from chloroform-n-hexane as 20 mg of yellow crystallinepowder of 6-0-(3'-chloropropyl)streptovaricinone C, m.p. 145°-147° C.

EXAMPLE 7 Preparation of the aldol compound of6-0-acetonyl-streptovaricinone C

To a solution of 2.70 g of 6-0-acetonylstreptovaricinone C in a mixedsolution of 70 ml of benzene and 14 ml of acetic acid was added 3.74 gof benzylamine. The reaction mixture was stirred at room temperature for30 minutes, and then diluted with 200 ml of benzene. The solution waswashed with water three times, dried over anhydrous sodium sulfate, andevaporated to dryness under reduced pressure to give a red oil. The oilwas chromatographed on silica gel with 3% methanol in chloroform, andthe appropriate fractions collected. After the combined fraction wasevaporated to dryness under reduced pressure, the residue wasrecrystallized from ethyl acetate-n-hexane to afford 2.05 g of orangecrystalline powder of the aldol of 6-0-acetonylstreptovaricinone C, m.p.162°-163° C.

EXAMPLE 8 Preparation of the aldol compound of6-0-phenacylstreptovaricinone C

To a solution of 208 mg of 6-0-phenacylstreptovaricinone C in a mixedsolution of 10 ml of benzene and 2 ml of acetic acid was added 200 mg ofpiperidine, and the reaction mixture was stirred at room temperature for20 hours. The solution was then diluted with 100 ml of ethyl acetate.The solution was washed with water three times followed by a salinesolution, dried over anhydrous sodium sulfate, and evaporated to drynessunder reduced pressure. The resulting red oil was recrystallized fromchloroform-n-hexane to afford 120 mg of orange red crystalline powder ofthe aldol compound of 6-0-phenacylstreptovaricinone C, m.p. 164°-166° C.

EXAMPLE 9 Preparation of the oxime of the aldol compound from6-0-acetonylstreptovaricinone C (Method A)

To a solution of 385 mg of 6-0-acetonylstreptovaricinone C in 10 ml ofbenzene was added 330 mg of hydroxylamine and 2 ml of acetic acid in 5ml of benzene, and the mixture was stirred at room temperature for 30minutes. The resulting mixture was evaporated to dryness under reducedpressure, and the residue was chromatographed on silica gel with 10%methanol in chloroform. The appropriate fractions were collected,combined, and evaporated to dryness under reduced pressure to give a redoil which was recrystallized from ethyl acetate-n-hexane as 161 mg oforange yellow crystals of the product, m.p. 189°-190° C.

EXAMPLE 10 Preparation of the oxime of the aldol compound of6-0-acetonylstreptovaricinone C (Method B)

To a solution of 385 mg of the aldol compound of6-0-acetonylstreptovaricinone C in 10 ml of methanol was added 347 mg ofhydroxylamine hydrochloride, and the mixture was stirred at roomtemperature for 1.5 hour. The resulting mixture was diluted with 40 mlof ethyl acetate, and the solution was washed with aqueous sodiumbicarbonate solution three times, dried over anhydrous sodium sulfate,and evaporated to dryness under reduced pressure to give a red oil. Theoil was chromatographed on silica gel with 5% methanol in chloroform,and the appropriate fractions were collected, combined, and evaporatedto dryness under reduced pressure to furnish a red oil which wasrecrystallized from ethyl acetate-n-hexane as 249 mg of the product,m.p. 189°-190° C. The product showed the same Rf value on t.l.c., IRspectrum (KBr), and melting point as those of the one obtained inExample 1.

EXAMPLE 11 Preparation of the N,N-dimethylhydrazone of aldol compound of6-0-acetonylstreptovaricinone C

To a solution of 385 mg of the aldol compound of6-0-acetonylstreptovaricinone C in 10 ml of benzene was added 30 mg ofN,N-dimethylhydrazine hydrochloride, and the mixture was stirred at roomtemperature for 1 hour. The mixture was then diluted with 30 ml ofbenzene. The mixture was washed with water twice, dried over anhydroussodium sulfate, and evaporated to dryness under reduced pressure to givea red oil. The oil was chromatographed on Sephadex LH-20 with methanol,and the appropriate fractions were collected, combined, and evaporatedto dryness to furnish a red oil which was recrystallized from ethylacetate-n-hexane to afford 110 mg of yellow crystalline powder of theproduct, m.p. 166°-167° C.

EXAMPLE 12 Preparation of N,N-di-n-pentylhydrazone of the aldol compoundof 6-0-streptovaricinone C

To a solution of 385 mg of 6-0-acetonylstreptovaricinone C in 10 ml ofbenzene was added 860 mg of 1,1-di-n-pentylhydrazine and 2 ml of aceticacid, and the mixture was stirred at room temperature for 30 minutes.The resultant reaction mixture was diluted with 30 ml of benzene, washedwith water three times, dried over anhydrous sodium sulfate, andevaporated to dryness under reduced pressure to give a red oil. The oilwas chromatographed on Sephadex LH-20 with acetone, and the appropriatefractions were collected, combined, and evaporated to dryness to affordan oil. The oil was recrystallized from ethyl acetate-n-hexane as 230 mgof N,N-di-n-pentylhydrazone of the aldol compound of6-0-acetonylstreptovaricinone C, m.p. 132°-133° C.

EXAMPLE 13 Preparation of 6-0-acetonylstreptovaricinone C O-n-butyloxime

To a solution of 200 mg of 6-0-acetonylstreptovaricinone C in 10 ml ofmethanol was added 125 mg of 0-n-butylhydroxylamine hydrochloride, andthe mixture was stirred at room temperature for 2 hours. The resultantmixture was diluted with 200 ml of ethyl acetate and the solution waswashed with water, dried over anhydrous sodium sulfate, and evaporatedto dryness under reduced pressure to give an orange oil which wasrecrystallized from acetone-n-hexane to afford 146 mg of yellow needlesof the O-n-butyloxime, m.p. 130°-132° C.

EXAMPLE 14 Preparation of 6-0-acetonylstreptovaricinone C 0-benzyloxime

To a solution of 256 mg of 6-0-acetonylstreptovaricinone C in 15 ml ofmethanol was added 100 mg of 0-benzylhydroxylamine hydrochloride, andthe reaction mixture was stirred at room temperature for 45 minutes. Theresultant mixture was diluted with 200 ml of ethyl acetate, washed withwater repeatedly, dried over anhydrous sodium sulfate, and evaporated todryness under reduced pressure to give a red oil. The oil waschromatographed on silica gel with 4% methanol in chloroform, and theappropriate fractions were collected, combined, and evaporated todryness to give an orange oil which was recrystallized fromacetone-n-hexane to afford 198 mg of yellow needles of theO-benzyloxime, m.p. 144°-145° C.

EXAMPLE 15 Preparation of 6-0-acetonylstreptovaricinone C semicarbazone

To a solution of 231 mg of 6-0-acetonylstreptovaricinone C in 15 ml ofmethanol was added 45 mg of semicarbazide hydrochloride, and thereaction mixture was stirred at room temperature for 30 minutes. Theresultant mixture was evaporated to dryness under reduced pressure, andthe resulting oil was chromatographed on silica gel with 10% methanol inchloroform. The appropriate fractions were collected, combined, andevaporated to dryness under reduced pressure to give an orange oil whichwas recrystallized from ethyl acetate-n-hexane as 115 mg of yellowcrystalline powder of 6-0-acetonylstreptovaricinone C semicarbazone,m.p. 235°-236° C.

EXAMPLE 16 Preparation of 6-0-acetylstreptovaricinone C

To a suspension of 363 mg of streptovaricinone C in 10 ml of acetone wasadded 10 ml of 0.05 N methanolic sodium hydroxide solution, and thesolution was evaporated to dryness under reduced pressure to obtain asodium salt of streptovaricinone C. The sodium salt was suspended in 20ml of dry tetrahydrofuran, and to the suspension was added 90 mg ofacetyl chloride. The reaction mixture was stirred at room temperaturefor 5 minutes, and then poured into 5% cold sodium bicarbonate solution.The mixture was extracted with benzene repeatedly, and the combinedextract was washed with water, dried over anhydrous sodium sulfate, andevaporated to dryness under reduced pressure to give a red oil. The oilwas chromatographed on silica gel with 5% methanol in chloroform, andthe appropriate fractions were collected and combined. The fraction wasevaporated to dryness under reduced pressure to afford an orange oilwhich was recrystallized from acetone-n-hexane as 182 mg of6-0-acetylstreptovaricinone C, m.p. 169°-171° C.

EXAMPLE 17 Preparation of 6-0-(3',5'-dinitrobenzoyl)-streptovaricinone CTo a suspension of 360 mg of streptovaricinone C in 30 ml of methanolwas added 10 ml of 0.05N methanolic sodium hydroxide solution, and themixture was stirred for 15 minutes and evaporated to dryness underreduced pressure to form the sodium salt. The sodium salt was thensuspended in 10 ml of dry tetrahydrofuran, and to the suspension wasadded 116 mg of 3,5-dinitrobenzoyl chloride, and the mixture was stirredat room temperature for 30 minutes, and evaporated to dryness underreduced pressure. The residue was dissolved in ethyl acetate, and thesolution was washed with water, dried over anhydrous sodium sulfate, andevaporated to dryness under reduced pressure. The residue waschromatographed on Sephadex LH-20 with acetone, and the appropriatefractions were collected and combined. The fraction was evaporated todryness under reduced pressure to give an orange red oil which wasrecrystallized from chloroform-n-hexane to afford a yellow crystallinepowder of 6-0-(3',5'-dinitrobenzoyl)streptovaricinone C, m.p. 178°-182°C. EXAMPLE 18 Preparation of 6-0-methanesulfonylstreptovaricinone C

To a suspension of 372 mg of streptovaricinone C in 10 ml of acetone wasadded 10 ml of 0.05N methanolic sodium hydroxide solution, and thesolution was evaporated to dryness under reduced pressure to obtain thesodium salt of streptovaricinone C. The sodium salt was suspended in 20ml of dry tetrahydrofuran, and to the suspension was added 138 mg ofmethanesulfonyl chloride in 10 ml of dry tetrahydrofuran, and thereaction mixture was stirred at room temperature for 48 hours, and thenpoured into 5% cold sodium bicarbonate solution. The mixture wasextracted with ethyl acetate, and the extract was washed with water,dried over anhydrous sodium sulfate, and evaporated to dryness to give ared oil. The oil was chromatographed on silica gel with 4% methanol inchloroform, and the appropriate fractions were collected, and combined.The fraction was evaporated to dryness under reduced pressure to affordan orange oil which was recrystallized from ethyl acetate-n-hexane togive 57 mg of yellow crystalline powder of6-0-methanesulfonylstreptovaricinone C, m.p. 167° -170° C.

EXAMPLE 19 Preparation of 6-0-methoxycarbonylstreptovaricinone C

To a suspension of 373 mg of streptovaricinone C in 10 ml oftetrahydrofuran was added 10 ml of 0.05N methanolic sodium hydroxidesolution, and the solution was evaporated to dryness under reducedpressure to obtain the sodium salt of streptovaricinone C. The salt wassuspended in 8 ml of tetrahydrofuran, and to the suspension was added145 mg of methyl chlorocarbonate. The reaction mixture was stirred atroom temperature for 30 minutes, and poured into 5% cold sodiumbicarbonate solution. The mixture was then extracted with ethyl acetaterepeatedly, and the extract was washed with water, dried over anhydroussodium sulfate, and evaporated to dryness under reduced pressure to givea red oil. The oil was chromatographed on silica gel with 7% methanol inchloroform, and then the appropriate fractions were collected andcombined. The fraction was evaporated to dryness under reduced pressureto afford an oil which was recrystallized from ethyl acetate-n-hexane togive 263 mg of a yellow crystalline powder of6-0-methoxycarbonylstreptovaricinon C, m.p. 159°-163° C.

Having now fully described the invention, it will be apparent to one ofordinary skill in the art that many changes and modifications can bemade thereto without departing from the spirit or scope of the inventionas set forth herein.

What is claimed as new and intended to be secured by Letters Patentis:
 1. A streptovaricinone C derivative of the formula: ##STR42##wherein Z is alkyl, a phenyl or a phenyl substituted by a halogen, analkoxy group, an alkyl group or NO₂, a hydroxyalkyl, an alkenyl, aketonyl having the formula ##STR43## wherein R' is a lower alkyl groupcontaining up to 6 carbon atoms, a phenyl group, a 2-furyl group, anα-thienyl group, and substituted derivatives thereof, wherein thesubstituent is a C₁ -C₆ alkyl group, a C₁ -C₆ alkoxy group, an hydroxylgroup, a nitro group or a halogen, a furyl-oxoalkyl, a thienyl-oxoalkyl,a phenacyl, a carbamylalkyl, a benzyl, a phenoxyalkyl, a cyanoalkyl, aphenethyl, a benzoyloxyethyl, a p-chlorophenacyl, a p-methoxyphenacyl, ap-nitrobenzyl, a p-methylbenzyl, an alkanoyl, a benzoyl, abenzenesulfonyl, an alkylsulfonyl or an alkoxy-carbonyl group whereinalkyl, alkoxy, alkenyl, alkanoyl and alkoxycarbonyl have 1-12 carbonatoms unless otherwise specified.
 2. The streptovaricinone C derivativesof claim 1, wherein Z is ##STR44## and R is hydroxyimino, hydroxyiminowherein O is substituted with a C₁₋₉ alkyl group, allyl, benzyl, --CH₂CH₂ OOC--C₆ H₅ or --CH₂ CH₂ --O--C₆ H₅, hydrazono or a hydrazono,=N--NR"R'", wherein R" and R'" are the same or different and each isC₁₋₈ alkyl, benzyl, phenyl, benzylidene, cyclohexylidene, allyl oramido, or NR"R'" together forms a piperazine ring, a morpholine ring, apiperidine ring or a methyl derivative thereof, a pyrrolidine ring,##STR45##
 3. The streptovaricinone C derivatives of claim 1, wherein Zis an alkanoyl, a benzoyl, a benzenesulfonyl, an alkylsulfonyl, analkoxycarbonyl group, or derivatives thereof having inert substituentsselected from the group consisting of halo, alkoxy or NO₂.
 4. A processfor producing a streptovaricinone C derivative of claim 1 whichcomprises etherifying the 6-position of streptovaricinone C with ahalide of the desired etherifying group in the presence of silver oxidein an inert solvent
 5. A process for producing a streptovaricinone Cderivative of claim 1 which comprises esterifying the 6-position of analkali metal salt of streptovaricinone C with an organic acid halide, anorganic sulfonic acid halide or an alkyl halocarbonate which reactantsprovide the ester group Z.
 6. A process for producing astreptovaricinone C derivative of claim 2 which compriseseffecting theetherification process of claim 4 wherein said halide is acetone halide;and then reacting the 6-0-acetonylstreptovariconone C product of saidetherification with hydroxylamine, an O-substituted hydroxylamine orhydrazine or a substituted hydrazine, which reactants provide thesubstituent R.
 7. An aldol condensation product of the streptovaricinoneC derivative of claim 1 having the formula: ##STR46## wherein R' is alower alkyl group containing up to 6 carbon atoms, a phenyl group, a2-furyl group, an α-thienyl group, and substituted derivatives thereof,wherein the substituent is a C₁ -C₆ alkyl group, a C₁ -C₆ alkoxy group,an hydroxyl group, a nitro group or a halogen.
 8. The aldol condensationproduct of claim 7 wherein R' is CH₃.
 9. An aldol condensation productof the streptovaricinone C derivative of claim 1 having the formula:##STR47## wherein R' is a lower alkyl group containing up to 6 carbonatoms, a phenyl group, a 2-furyl group, an α-thienyl group, andsubstituted derivatives thereof wherein the substituent is a C₁ -C₆alkoxy group, an hydroxyl group, a nitro group or a halogen, and R ishydroxyimino, hydroxyimino wherein O is substituted with a C₁₋₉ alkylgroup, allyl, benzyl, --CH₂ CH₂ OOC--C₆ H₅ or --CH₂ CH₂ --O--C₆ H₅,hydrazono or a hydrazono, =N-NR" R'", wherein R" and R'" are the same ordifferent and each is C₁₋₈ alkyl, benzyl, phenyl, benzylidene,cyclohexylidene, allyl or amido, or NR" R'" together forms a piperazinering, a morpholine ring, a piperidine ring or a methyl derivativethereof, a pyrrolidine ring, ##STR48##
 10. The aldol condensationproduct of claim 9 wherein R' is CH₃.
 11. A pharmaceutical compositionwhich comprises an antibiotically effective amount of astreptovaricinone C derivative of claim 1 and a pharmaceuticallyacceptable carrier.
 12. A pharmaceutical composition which comprises anantibiotically effective amount of a streptovaricinone C derivative ofclaim 7 and a pharmaceutically acceptable carrier.
 13. A pharmaceuticalcomposition which comprises an antibiotically effective amount of astreptovaricinone C derivative of claim 9 and a pharmaceuticallyacceptable carrier.
 14. A pharmaceutical composition which comprises anantibiotically effective amount of a streptovaricinone C derivative ofclaim 2 and a pharmaceutically acceptable carrier.